Treatment Of Melanoma Skin Cancer Research Articles

Molecular docking studies for NPACT ligands for the treatment of melanoma skin cancer

Approximately 80% of deaths attributable to skin cancer are attributed to melanoma. The main reason for its life-threatening nature is its high tendency to metastasis. The outlook for melanoma patients with distal metastases is grim, as they have a median survival of only six months, despite the utilization of the most advanced treatments now available. The Extracellular signal-regulated kinase (ERK) pathway is the most frequently altered oncogene in melanoma. Phytochemicals are receiving significant recognition due to their minimal toxicity, affordable price, and widespread acceptance as dietary supplements. Preclinical investigations have revealed many cellular and molecular processes via which phytochemicals function in the prevention and treatment of metastatic melanoma.: In this study, we performed virtual screening of 464 phytoconstituents were obtained from the Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target (NPACT) database to identify novel ERK inhibitors.: Virtual screening carried out prediction of drug-likeness and molecular docking studies with 2OJG, protein target related to ERK pathway.: Nine compounds achieved better docking score as compared to co-crystallized ligand. The accuracy of the docking method was checked using re-docking. Picetannol and sulfurentin were identified as potential inhibitors with docking score of -9.2 and -8.2, respectively. These two phytoconstituents also found to be non-carcinogenic which was predicted using a free webtool, Swiss ADME.: Our finding suggests that Piceatannol has promising potential to be further explored as ERK-pathway inhibitor in treatment of melanoma

Molecular Docking Studies for Evaluation of Amaranth Grain Squalene for Treatment of Melanoma Skin Cancer in Human Beings

Abstract: The main purpose of the present study is to check the therapeutic role of Amaranth squalene against skin cancer by performing docking studies with TGF-β, MIA and Raf which are important target proteins of signal transduction pathways leading to skin cancer development in human beings. In accordance with the World Health Organization, one of the leading causes of death worldwide is cancer. Discovering alternative, economical, and effective cancer treatment options is essential due to the high cost of the currently existing cancer therapies and other treatment-related constraints. Grains of Amaranth, a nutritionally important pseudocereal, are rich in squalene which possess important pharmacological properties. Due to the presence of squalene, Amaranth grain can be used as food based therapy for many dreadful diseases including cancer. Melanoma type of skin cancer is a serious form of skin cancer which is responsible for high mortality rate world wide. At present, Vemurafenib, which binds Braf and commonly used as drug for treatment of skin cancer has various adverse effects. Therefore, in the current investigation, the interaction of squalene a terpenoid compound from Amaranth, with proteins of skin cancer signalling pathway such as TGF-beta, Braf, and M.I.A was studied through molecular docking conducted by using Autodock vina software. To check the therapeutic role of Amaranth squalene against skin cancer by performing docking studies with TGF-β, MIA and Raf which are important target proteins of signal transduction pathway leading to skin cancer development in human beings. The 3D crystal structures of the proteins examined in this investigation were queried from The Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) Web server (https:// www. rcsb. org/). For the present study, three proteins were taken, TGF-Beta (PDB ID:3tzm. MIA (PDB ID: 5ixb, BRAF (PDB ID:5jrq. The structure of squalene was taken from the PubChem database and was converted from .sdf format to .pdb format using Open- Babel. pkCSM (http:// structure. bioc.cam. ac.uk/pkcsm) along with SwissADME (http:// www. swiss adme.ch/ index. php) websites were used for Drug-likeliness properties of the compound. Anticancerous behaviour of Squalene was predicted with support of software PASS. Active Site of target Protein was projected by Biovia Drug Discovery Studio Visualizer 2020 (PDB ID: (TGF-β: 3tzm), (MIA: 5ixb), (BRAF: 5jrq). Protein-ligand docking studies were performed using the AutoDock v4.2.6 program. On the basis of the docking score, it was revealed that Amaranth squalene strongly interacted with Braf (5jrq) with binding energy of -14.4 followed by TGF-beta (3tzm) and MIA (5ixb) as compared to well-known drug Vemurafenib which has a binding energy of -4.9 only. Moreover, squalene ligand satisfied Lipinski’s rule of 5. Squalene may have enzyme-inhibitory action according to docking results and also be useful in in-vivo anti-cancerous screenings on model organisms. The present study demonstrated the therapeutic potential of Amaranth Squalene in the prevention of skin cancer as revealed by it’s stronger interaction with BRAF, TGF-β and MIA proteins as compared to Vemurafanib, a well-known drug used to treat skin cancer. The studies paved the way for Squalene to have a potential drug. Since Amaranth grains possess are enriched with squalene, the nutraceuticals/ food prepared from them has high prospectus to be used as a food based therapy for skin cancer treatment.

Circulating vitamin D concentration and risk of 14 cancers: a bidirectional Mendelian randomization study.

Observational studies have revealed relationships between circulating vitamin D concentrations and the risk of different types of cancer, although the potential causal relationship remains controversial. This study aims to investigate the presence of a causal relationship between circulating vitamin D concentrations and the risk of different types of cancer. Summary statistics from corresponding genome-wide association studies (GWASs) were used to investigate the causal relationship between circulating vitamin D concentrations and the risk of 14 cancers. A two-sample Mendelian randomization (MR) analysis using inverse-variance weighting (IVW) as the primary method was performed. Additionally, the results were verified using four other methods, including MR-Egger, weighted median, weighted mode, and simple mode. Multiple sensitivity analyses were conducted to ensure the robustness of our MR findings. The MR analysis showed no causal relationship between circulating vitamin D concentrations and most types of cancer, except for a causal relationship with melanoma skin cancer (MSC) (odds ratio [OR]IVW = 1.003, 95% confidence intervals [CI] 1.001-1.005, P = 0.004). Conversely, reverse MR revealed a causal relationship between circulating vitamin D concentration and colorectal cancer (ORIVW = 0.398, 95% CI 0.195-0.813, P = 0.01; ORweighted median = 0.352, 95% CI 0.135-0.917, P = 0.03). Our findings provide support for a causal relationship between circulating vitamin D concentration and risk of MSC. Additionally, we found a causal relationship between circulating vitamin D concentration and risk of colorectal cancer in reverse-MR analysis. This evidence indicate that vitamin D is of great significance in the prevention and treatment of MSC and the prognosis of colorectal cancer.

Enzymatic depletion of l-Met using an engineered human enzyme as a novel therapeutic strategy for melanoma.

Many cancers, including melanoma, have a higher requirement for l-methionine in comparison with noncancerous cells. In this study, we show that administration of an engineered human methionine-γ-lyase (hMGL) significantly reduced the survival of both human and mouse melanoma cells in vitro. A multiomics approach was utilized to identify global changes in gene expression and in metabolite levels with hMGL treatment in melanoma cells. There was considerable overlap in the perturbed pathways identified in the two data sets. Common pathways were flagged for further investigation to understand their mechanistic importance. In this regard, hMGL treatment induced S and G2 phase cell cycle arrest, decreased nucleotide levels, and increased DNA double-strand breaks suggesting an important role for replication stress in the mechanism of hMGL effects on melanoma cells. Further, hMGL treatment resulted in increased cellular reactive oxygen specieslevels and increased apoptosis as well as uncharged transfer RNApathway upregulation. Finally, treatment with hMGL significantly inhibited the growth of both mouse and human melanoma cells in orthotopic tumor models in vivo. Overall, the results of this study provide a strong rationale for further mechanistic evaluation and clinical development of hMGL for the treatment of melanoma skin cancer and other cancers.

Paclitaxel loaded transfersomal vesicular drug delivery for the treatment of melanoma skin cancers

Over the last few years, there is tremendous growth of melanoma skin cancer in all around the world. Paclitaxel is an antineoplastic drug which is widely used for breast cancer, lung cancer, and Kaposi sarcoma. It is available only in the form of intravenous (IV), which produces tissue damage and hypersensitivity in some patients if the dose is over. In the present article, the new initiative formulation is done for melanoma skin cancer with transfersomes drug delivery systems. A different formulation of transfersomes is prepared using Span. The various characterization is done for the transfersomes like morphology, entrapment efficacy, in vitro drug release dialysis bag method. By using the Carbopol 940, the transfersomes gel was prepared. Paclitaxel-loaded transfersomes (FS-2) shows the positive entrapment efficacy 68.2% and the vesicle size 200 nm. From the in vitro dialysis bag method, FS-2 showed the high rate of drug release by nearly 72% in 12 hrs. we conclude that this will be the initial step for the further studies of melanoma skin cancer and provide the better treatment for skin cancer.

Curcumin Loaded Ethosomal Vesicular Drug Delivery System for the Treatment of Melanoma Skin Cancer

Curcumin has an excellent safety profile having various pleiotropic actions, including anti-inflammatory, antioxidant, antitumoral, anticancer, and antimicrobial activities, with the potential for neuroprotective activity but the poor oral bioavailability limits its use as oral dosage form. The purpose of this study was to formulate and evaluate the transdermal drug delivery system of Ethosomes containing curcumin, a potent anti-cancer drug. Study on various formulation excipients revealed that all the excipients shown some variation which affected the vesicle size, zeta potential, PDI and entrapment efficiency. Batch prepared with 10 % of soya lecithin, 4.5 % of ethanol and 10% of cholesterol showed maximum entrapment efficiency of 81.2±3.12.In in vitro drug permeation studies using dialysis bag, the samples withdrawn in equal time intervals shown more drug release from the dialysis bag in comparison with that of inhouse paclitaxel gel which conform that the curcumin loaded ethosomal gel is a better formulation for the further studies. In ex vivo, permeation study using pork ear skin, curcumin loaded ethosomal gel showed the greater drug deposition on the skin > 60 % in 12 hrs for the better curability for the melanoma. Whereas inhouse paclitaxel gel shown < 60 % of drug deposition in 12 h. The comparison of both ethosomal gel and inhouse paclitaxel gel reveals that ethosomal gel shown maximum release within 12 hrs in both in vitro and ex vivo studies, which can be taken for the further in vitro cell line and in vivo study.

Selective Toxicity of Non Polar Bioactive Compounds of Persian Gulf Sea Squirt Phallusia Nigra on Skin Mitochondria Isolated from Rat Model of Melanoma

Background:Skin cancer is the most prevalent cancer and one of the major causes of mortality worldwide. Marin animals have attracted much attention in recent years as useful substances having application in medicine. It was shown that Phallusia nigra (P. nigra) known as sea squirt could play an important role in cancer therapy.Methods:This study was designed to figure out the probable selective toxicity of n-hexane, diethyl ether, methanolic and aqueous extracts of P. nigra on cancerous mitochondria isolated from the skin of melanoma induced rats. In our study, mitochondria were isolated from the skin tissue of both melanoma induced and normal healthyrats. Different concentrations of four different extracts of P. nigra (250, 500 and 1000 µg/ml) were added to mitochondrial samples obtained from both groups, separately.Results:Our results showed that n-hexane, diethyl ether and methanolic extracts (but not aqueous extract) of P. nigra in all concentrations applied (250, 500 and 1000 µg/ml) significantly induced toxic alterations only in the cancerous but not normal healthy skin mitochondria including; increased reactive oxygen species (ROS) formation, mitochondrial swelling, decreased mitochondrial membrane potential (MMP) and cytochrome c release. Flow-cytometry analysis demonstrated that n-hexane, diethyl ether and methanolic extracts of P. nigra progressively induced apoptosis and necrosis only on melanoma cells but not healthy skin cells.Conclusions:Our results suggest that non polar bioactive compounds in P. nigra may be hopeful candidates for further studies including molecular identification, confirmatory in vivo experiments and finally clinical trials designed for new drug treatment of melanoma skin cancer.

Current and Next Generation Topical Anti-Skin Cancer Therapeutics

Non-melanoma skin cancers are among the most commonly diagnosed skin cancers in the world. Ultraviolet radiation is a primary carcinogen resulting in UV induced mutations, loss of activity in tumour suppressor genes and the over expression of oncogenes in keratinocytes resulting in the development of skin malignancies. With the continued rising rate of non-melanoma skin cancer, topical therapies have become an established treatment method for effective lesion clearance. Current topical therapies include 5-fluorouracil, imiquimod, diclofenac, ingenol mebutate and photodynamic therapy. With high lesion recurrence rates still presenting as an issue following topical treatment, lack of drug selectivity for cancer cells, severe side effects from topical agent use and patient non-compliance due to prolonged treatment periods, new novel topical therapies need to be explored and developed. New therapies must target and clear both subclinical and clinically presenting skin cancers by interrupting the molecular mechanisms that induce and sustain the proliferation of neoplastic cells. Piperlongumine and EBC-46 are two naturally occurring small molecules which have demonstrated effective induction of cancer cell death. Piperlongumine, an amide isolated from the pepper, Piper longum, has demonstrated cancer cell death selectivity yet has no impact on healthy rapidly dividing primary cells. EBC-46 is a diterpene ester isolated from the seed of the fruit, Fontainea picrosperma. EBC-46 induces rapid inflammation and necrosis resulting in tumour ablation following intra-lesional injection. The development of Piperlongumine and EBC-46, as new topical agents offers a unique opportunity to further explore and exploit these selective properties for a more efficient and targeted approach to topical non -melanoma skin cancer treatment.

The Complexity of the ERK/MAP-Kinase Pathway and the Treatment of Melanoma Skin Cancer.

The central role played by the ERK/MAPK pathway downstream of RAS in human neoplasias is best exemplified in the context of melanoma skin cancer. Signaling through the MAPK pathway is crucial for the proliferation of melanocytes, the healthy pigment cells that give rise to melanoma. However, hyper-activation of the MAPK-pathway is found in over 90% of melanomas with approximately 50% of all patients displaying mutations in the kinase BRAF, and approximately 28% of all patients harboring mutations in the MAPK-pathway up-stream regulator NRAS. This finding has led to the development of BRAF and MEK inhibitors whose application in the clinic has shown unprecedented survival responses. Unfortunately the responses to MAPK pathway inhibitors are transient with most patients progressing within a year and a median progression free survival of 7–10 months. The disease progression is due to the development of drug-resistance based on various mechanisms, many of them involving a rewiring of the MAPK pathway. In this article we will review the complexity of MAPK signaling in melanocytic cells as well as the mechanisms of action of different MAPK-pathway inhibitors and their correlation with clinical response. We will reflect on mechanisms of innate and acquired resistance that limit patient's response, with a focus on the MAPK signaling network. Because of the resurgence of antibody-based immune-therapies there is a growing feeling of failure in the targeted therapy camp. However, recent studies have revealed new windows of therapeutic opportunity for melanoma sufferers treated with drugs targeting the MAPK pathway, and these opportunities will be discussed.

Photodynamic therapy of melanoma skin cancer using carbon dot – chlorin e6 – hyaluronate conjugate

Despite wide application of photodynamic therapy (PDT) for the treatment of melanoma skin cancers, there are strong biomedical unmet needs for the effective generation of singlet oxygen after targeted delivery of photosensitizers. Here, we investigated a facile PDT of melanoma skin cancer using transdermal carbon dot – chlorine e6 – hyaluronate (Cdot-Ce6-HA) conjugates. The Cdot-Ce6-HA conjugate was synthesized by the coupling reaction of diaminohexane modified HA (DAH-HA) with the carboxylic group of Ce6. The singlet oxygen generation of Cdot-Ce6-HA conjugates in aqueous solution was more significant than that of free Ce6. The enhanced transdermal and intracellular delivery of Cdot-Ce6-HA conjugates to B16F10 melanoma cells in tumor model mice were corroborated by confocal microscopy and two-photon microscopy. The laser irradiation after topical treatment with Cdot-Ce6-HA conjugates resulted in complete suppression of melanoma skin cancers. The antitumor effect was confirmed by histological analysis with H&E staining and TUNEL assay for tumor apoptosis. Taken together, we could confirm the feasibility of Cdot-Ce6-HA conjugate for transdermal PDT of melanoma skin cancers. Statement of SignificanceTo our knowledge, this is the first report on a facile transdermal photodynamic therapy (PDT) of melanoma skin cancer using carbon dot – chlorine e6 – hyaluronate (Cdot-Ce6-HA) conjugates.We found that the singlet oxygen generation of Cdot-Ce6-HA conjugates in aqueous solution was more significant than that of free Ce6.Confocal microscopy and two-photon microscopy clearly confirmed the enhanced transdermal and intracellular delivery of Cdot-Ce6-HA conjugates to B16F10 melanoma cells in tumor model mice.Taken together, we could confirm the feasibility of Cdot-Ce6-HA conjugate for transdermal PDT of melanoma skin cancers.

Purification and N-Glycosylation Analysis of Melanoma Antigen Dopachrome Tautomerase

Dopachrome tautomerase (DCT) plays a critical role in lowering the oxidative stress resulting from melanogenesis. Levels of DCT are elevated in melanoma cell lines that are especially resistant to chemotherapy and radiation. DCT is processed as a melanoma antigen and is a potential target for immunotherapy. In order to establish a more complete understanding of the role that DCT may play in the etiology and treatment of melanoma skin cancer, isolation of highly pure and properly processed protein is necessary. Purification of native DCT has been problematic due to a hydrophobic transmembrane anchor and interactions with melanin. In this study, DCT was expressed, without its carboxy-terminal transmembrane region using an Sf9 insect cell protein expression system and its recombinant protein was purified by various chromatographic techniques. Analysis of DCT tryptic peptides by MALDI-TOF/TOF determined N-glycosylation as a primary post-translational modification. Our success in the expression of soluble mammalian DCT and the characterization of N-glycosylation sites is a useful reference toward the comprehensive understanding of the structure/function relationship of mammalian DCT.